Four recent randomized controlled trials of endovascular reperfusion therapy administered to stroke patients within 6 hours after symptom onset have demonstrated decisive clinical benefits. The next clinical imperative is to determine whether endovascular therapy is safe and effective in an extended time window. In addition, if it is effective, it is essential to determine how to optimally select patients for endovascular therap in extended time windows. The Diffusion and Perfusion Weighted Imaging Evaluation for Understanding Stroke Evolution study (DEFUSE) demonstrated that pre-specified baseline magnetic resonance imaging (MRI) profiles can identify stroke patients who have a sizeable clinical response after early reperfusion in an extended time window. DEFUSE 2 prospectively validated the DEFUSE findings by demonstrating that patients with favorable MRI profiles who achieved early reperfusion after endovascular therapy had significantly better clinical outcomes up to 12 hours after onset; the adjusted odds ratio for favorable clinical response associated with reperfusion was 8*8 (95% CI 2*7-29*0). Recent studies have demonstrated that CT Perfusion has comparable accuracy to MRI for identifying patients with salvageable tissue. DEFUSE 3 is a prospective, randomized, multicenter trial of patients with an acute ischemic stroke who can be treated between 6 and 16 hours of stroke onset. Patients who meet the inclusion criteria will undergo an MRI or CT Perfusion scan prior to randomization. If patients have evidence of a major vessel occlusion and imaging evidence of salvageable tissue on MRI or CT perfusion, they will be randomized in a 1:1 ratio to treatment with an FDA cleared thrombectomy device (endovascular therapy) versus standard medical therapy alone. Randomization of a maximum of 476 patients (238/arm) is planned. A novel adaptive design will identify the largest subgroup, based on baseline DWI lesion volumes and the times since stroke onset, which show a positive effect from endovascular treatment. The results of DEFUSE 3 will determine if endovascular therapy improves functional outcome in stroke patients with favorable clinical and imaging characteristics. These results have the potential to increase the number of stroke patients who are eligible to receive an effective therapy, which could lead to a major reduction in stroke morbidity.